Osteoporosis is a major cause of morbidity among older Americans. The San Antonio Family Osteoporosis Study (SAFES) initiated in 1997 with the aim of identifying the determinants of bone mineral density (BMD) in large Mexican American families. A total of 897 subjects from 34 families were enrolled in the baseline phase of this study. Extensive genotypic information was made available on these subjects through their concurrent participation in a larger study, the San Antonio Family Heart Study (SAFHS), designed to identify the genetic determinants of atherosclerosis in these families. To date, we have obtained several exciting results from the SAFES. Foremost among these was the detection of very strong evidence for linkage of fore arm BMD to a region on chromosome 4p (multipoint led score = 4.3). We also observed associations of increased BMD with diabetes and of decreased BMD with carotid wall thickening, a subclinical measure of atherosclerosis in women aged 40 yr and older. This latter observation supports a growing body of evidence suggesting that osteoporosis and CVD share common etiologic determinants. We propose in the second 5-year funding period to re-measure BMD to assess 5-yr change in BMD and to begin fine mapp ng of the putative quantitative trait locus affecting BMD on chromosome 4p. Repeat DXA scans are currently being obtained in conjunction with the ongoing re-examination of SAFHS subjects. We will estimate hedtability of 5-yr changes in BMD and determine predictors of bone loss. We will utilize a positional candidate gene approach to pursue the major fine mapping aim. We will sequence coding and regulatory regions of 20 genes in the region of linkage to identify sequence variation and will then genotype all common variants in the full sample of SAFES participants for association and haplotype analysis.